Microbiocidal phenylamidine derivatives

Abstract

Compounds of the formula (I) wherein the subsitiuents are as defined in claim 1. Furthermore, the present invention relates to agrochemical compositions which comprise compounds of formula (I), to preparation of these compositions, and to the use of the compounds or compositions in agriculture or horticulture for combating, preventing or controlling infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, in particular fungi.

Claims

1. A compound of formula (I) ##STR00025## wherein R.sup.1 and R.sup.2 are each independently selected from C.sub.1-C.sub.4alkyl and C.sub.3-C.sub.8cycloalkyl; or R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached form a three- to six-membered saturated cyclic group; R.sup.3 is hydrogen, halogen or C.sub.1-C.sub.4 alkyl; R.sup.4 and R.sup.5 are each independently selected from hydrogen and C.sub.1-C.sub.4 alkyl; or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a carbonyl group (CO); X is O, S or NCH.sub.3; n is 0 or 1; or a salt, metal complex, stereoisomer or N-oxide thereof.

2. A compound according to claim 1 wherein R.sup.1 and R.sup.2 are each independently C.sub.1-C.sub.4 alkyl.

3. A compound according to claim 1 wherein R.sup.3 is halogen or C.sub.1-C.sub.3 alkyl.

4. A compound according to claim 1 wherein R.sup.4 and R.sup.5 are each independently selected from hydrogen and methyl, or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a carbonyl group.

5. A compound according to claim 1 wherein R.sup.1 and R.sup.2 are each independently selected from methyl, ethyl and isopropyl.

6. A compound according to claim 1 wherein R.sup.3 is fluoro, chloro or methyl.

7. A compound according to claim 1 wherein R.sup.4 and R.sup.5 are both hydrogen, or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a carbonyl group.

8. A compound according to claim 1 wherein R.sup.1 is methyl, ethyl or isopropyl and R.sup.2 is methyl or ethyl.

9. A compound according to claim 1 wherein R.sup.3 is chloro or methyl and R.sup.4 and R.sup.5 are both hydrogen.

10. A compound according to claim 1 wherein R.sup.1 and R.sup.2 are each independently selected from methyl, ethyl and isopropyl; R.sup.3 is fluoro, chloro or methyl; R.sup.4 and R.sup.5 are both hydrogen, or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a carbonyl group; X is O, S or NCH.sub.3; n is 0 or 1; or a salt, metal complex, stereoisomer or N-oxide thereof.

11. A compound according to claim 1 wherein the compound is selected from: ##STR00026## N-ethyl-N-[5-hydroxy-2-methyl-4-[2-(trifluoromethyl)tetrahydrofuran-2-yl]phenyl]-N-methyl-formamidine; ##STR00027## N-[5-hydroxy-2-methyl-4-[2-(trifluoromethyl)tetrahydrofuran-2-yl]phenyl]-N-isopropyl-N-methyl-formamidine; ##STR00028## N-[2-chloro-5-hydroxy-4-[2-(trifluoromethyl)tetrahydrofuran-2-yl]phenyl]-N-ethyl-N-methyl-formamidine; ##STR00029## N-ethyl-N-[5-hydroxy-2-methyl-4-[4-oxo-2-(trifluoromethyl)tetrahydrofuran-2-yl]phenyl]-N-methyl-formamidine; ##STR00030## N-ethyl-N-[5-hydroxy-2-methyl-4-[2-(trifluoromethyl)tetrahydrothiophen-2-yl]phenyl]-N-methyl-formamidine; or ##STR00031## N-ethyl-N-[5-hydroxy-2-methyl-4-[2-(trifluoromethyl)oxetan-2-yl]phenyl]-N-methyl-formamidine; or a salt, metal complex, stereoisomer or N-oxide thereof.

12. A compound according to claim 1 wherein X is O or S.

13. A composition comprising a fungicidally effective amount of a compound of formula (I) as defined in claim 1.

14. A composition according to claim 13, wherein the composition further comprises at least one additional active ingredient and/or a diluent.

15. A method of combating, preventing or controlling phytopathogenic fungi which comprises applying to phytopathogenic fungi, to the locus of phytopathogenic fungi, or to a plant susceptible to attack by phytopathogenic fungi, or to propagation material thereof, a fungicidally effective amount of a compound of formula (I) as defined in claim 1.

16. A method of combating, preventing or controlling phytopathogenic fungi which comprises applying to phytopathogenic fungi, to the locus of phytopathogenic fungi, or to a plant susceptible to attack by phytopathogenic fungi, or to propagation material thereof, a composition comprising a fungicidally effective amount of a compound of formula (I) as defined in claim 1.

Description

EXAMPLES

(1) The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.

(2) Throughout this description, temperatures are given in degrees Celsius and m.p. means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy.

(3) TABLE-US-00002 Formulation Examples Wettable powders a) b) c) active ingredient [compound of formula (I)] 25% 50% 75% sodium lignosulfonate 5% 5% sodium lauryl sulfate 3% 5% sodium diisobutylnaphthalenesulfonate 6% 10% phenol polyethylene glycol ether 2% (7-8 mol of ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27%
The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.

(4) TABLE-US-00003 Powders for dry seed treatment a) b) c) active ingredient [compound of formula (I)] 25% 50% 75% light mineral oil 5% 5% 5% highly dispersed silicic acid 5% 5% Kaolin 65% 40% Talcum 20
The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.

(5) TABLE-US-00004 Emulsifiable concentrate active ingredient [compound of formula (I)] 10% octylphenol polyethylene glycol ether 3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (35 mol of ethylene 4% oxide) Cyclohexanone 30% xylene mixture 50%
Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

(6) TABLE-US-00005 Dusts a) b) c) Active ingredient [compound of formula 5% 6% 4% (I)] talcum 95% Kaolin 94% mineral filler 96%
Ready-for-use dusts are obtained by mixing the active ingredient with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.

(7) TABLE-US-00006 Extruder granules Active ingredient [compound of formula (I)] 15% sodium lignosulfonate 2% carboxymethylcellulose 1% Kaolin 82%
The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.

(8) TABLE-US-00007 Coated granules Active ingredient [compound of formula (I)] 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.

(9) TABLE-US-00008 Suspension concentrate active ingredient [compound of formula (I)] 40% propylene glycol 10% nonylphenol polyethylene glycol ether 6% (15 mol of ethylene oxide) Sodium lignosulfonate 10% carboxymethylcellulose 1% silicone oil (in the form of a 75% emulsion 1% in water) Water 32%
The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

(10) TABLE-US-00009 Flowable concentrate for seed treatment active ingredient [compound of formula (I)] 40% propylene glycol 5% copolymer butanol PO/EO 2% tristyrenephenole with 10-20 moles EO 2% 1,2-benzisothiazolin-3-one (in the form of a 0.5% 20% solution in water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75 % emulsion 0.2% in water) Water 45.3%
The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
Slow Release Capsule Suspension
28 parts of a combination of the compound of formula (I) are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.
The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.
The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

PREPARATION EXAMPLES

Example 1: this example illustrates the preparation of N-ethyl-N-[5-methoxy-2-methyl-4-[2-(trifluoromethyl)tetrahydrofuran-2-yl]phenyl]-N-methyl-formamidine (Compound 1.22)

Preparation of N-ethyl-N-[5-methoxy-2-methyl-4-(2,2,2-trifluoroacetyl)phenyl]-N-methyl-formamidine

(11) N-(4-bromo-5-methoxy-2-methyl-phenyl)-N-ethyl-N-methyl-formamidine (6.0 g, 21.04 mmol) was dissolved in tetrahydrofuran (84 mL) and cooled to 78 C. A 2N n-butyl lithium solution in cyclohexane (18.9 mL, 37.87 mmol) was added dropwise. The resulting yellow solution was stirred for 1 h at 78 C. Ethyl 2,2,2-trifluoroacetate (8.97 g, 63.128 mmol) neat was added dropwise. At the end of the addition the cooling bath was removed and the reaction was warmed to 0-5 C. and then quenched with a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduce pressure.

(12) The residue was purified by chromatography on silica gel, using ethyl acetate/dichloromethane as eluent system, to deliver N-ethyl-N-[5-methoxy-2-methyl-4-(2,2,2-trifluoroacetyl)phenyl]-N-methyl-formamidine (5.1 g, 16.89 mmol).

(13) Major isomer: .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.27 (t, 3H), 2.22 (s, 3H), 3.08 (s, 3H), 3.41 (d, 2H), 3.90 (s, 3H), 6.36 (br. s, 1H), 7.56 (br. s, 2H)

(14) Minor isomer: .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.27 (t, 3H), 2.22 (s, 3H), 3.08 (s, 3H), 3.62 (d, 2H), 3.90 (s, 3H), 6.36 (br. s, 1H), 7.50 (s, 1H), 7.56 (br. s, 1H) Ratio E/Z: 3:5

Preparation of N-ethyl-N-[4-[1-hydroxy-1-(trifluoromethyl)allyl]-5-methoxy-2-methyl-phenyl]-N-methyl-formamidine

(15) To a solution of N-ethyl-N-[5-methoxy-2-methyl-4-(2,2,2-trifluoroacetyl)phenyl]-N-methyl-formamidine (2.00 g, 6.29 mmol) in tetrahydrofuran (7 mL) was added bromo(vinyl)magnesium (7.23 mL, 7.23 mmol) was added dropwise at 5 C. and the reaction mixture was stirred at 0 C. for 45 min. The reaction mixture was filtrated and poured on cooled water (15 mL), then aqueous ammonium chloride solution was added until disappearance of the precipitate and the mixture was extracted with ethyl acetate (320 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to afford N-ethyl-N-[4-[1-hydroxy-1-(trifluoromethyl)allyl]-5-methoxy-2-methyl-phenyl]-N-methyl-formamidine (2.20 g, 5.99 mmol). The material was used as crude for the next step.

(16) .sup.1H-NMR (400 MHz, CDCl.sub.3): =7.46 (1H, m), 7.07 (1H, s), 6.42 (2H, m), 6.31 (1H, s), 5.77 (1H, d), 5.52 (1H, d), 3.93 (3H, br s), 3.36 (2H, m), 3.03 (3H, s), 2.21 (3H, s), 1.24 (3H, t)

Preparation of N-[4-[1-allyloxy-1-(trifluoromethyl)allyl]-5-methoxy-2-methyl-phenyl]-N-ethyl-N-methyl-formamidine

(17) To a solution of N-ethyl-N-[4-[1-hydroxy-1-(trifluoromethyl)allyl]-5-methoxy-2-methyl-phenyl]-N-methyl-formamidine (2.25 g, 6.13 mmol) in N,N-dimethylformamide (24.5 mL) was added sodium hydride (0.258 g, 6.74 mmol) portionwise. The reaction mixture was stirred at room temperature for 30 min. Then, allyl bromide (0.536 mL, 6.13 mmol) was added dropwise and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched with slow addition of saturated ammonium chloride solution (20 mL) and then extracted with ethyl acetate (315 mL). The combined organic layers were washed with water (2100 mL), brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography on silica gel using (ethyl acetate/cyclohexane as eluent system, to deliver N-[4-[1-allyloxy-1-(trifluoromethyl)allyl]-5-methoxy-2-methyl-phenyl]-N-ethyl-N-methyl-formamidine (1.99 g, 5.3 mmol).

(18) .sup.1H-NMR (400 MHz, DMSO): =1.14 (t, 3H), 2.12 (s, 3H), 2.86-3.08 (m, 3H), 3.44 (m, 2H), 3.70 (s, 3H), 3.85 (d, 2H), 5.17 (dd, 1H), 5.33 (m, 2H), 5.49 (d, 1H), 5.93 (1H, m), 6.32 (dd, 1H), 6.52 (s, 1H), 7.17 (s, 1H), 7.59-7.86 (m, 1H)

Preparation of N-ethyl-N-[5-methoxy-2-methyl-4-[5-(trifluoromethyl)-2H-furan-5-yl]phenyl]-N-methyl-formamidine

(19) A solution of N-[4-[1-allyloxy-1-(trifluoromethyl)allyl]-5-methoxy-2-methyl-phenyl]-N-ethyl-N-methyl-formamidine (1.00 g, 2.7 mmol) in dichloromethane (54.0 mL) was degassed with argon before benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.113 g, 0.135 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum then the residue was taken-up in water (60 mL) and acidified with HCl 2M. The mixture was extracted with diethyl ether (220 mL) then the aqueous layer was basified with aqueous sodium bicarbonate solution (until pH 10).

(20) The solution was extracted with dichloromethane (320 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography on silica gel using (ethyl acetate/cyclohexane as eluent system to deliver N-ethyl-N-[5-methoxy-2-methyl-4-[5-(trifluoromethyl)-2H-furan-5-yl]phenyl]-N-methyl-formamidine (0.90 g, 2.6 mmol).

(21) .sup.1H-NMR (400 MHz, DMSO): =8.22-8.62 (1H, m), 7.49 (1H, s), 7.14 (2H, m), 6.26-6.69 (2H, m), 4.59-4.92 (2H, m), 3.86 (3H, s), 3.57-3.78 (2H, m), 3.28-3.36 (3H, m), 2.30 (3H, m), 1.28 (3H, t).

Preparation of N-ethyl-N-[5-methoxy-2-methyl-4-[2-(trifluoromethyl)tetrahydrofuran-2-yl]phenyl]-N-methyl-formamidine (Compound 1.22)

(22) A solution of N-ethyl-N-[5-methoxy-2-methyl-4-[5-(trifluoromethyl)-2H-furan-5-yl]phenyl]-N-methyl-formamidine (200 mg, 0.58 mmol) in ethanol (6 mL) was degassed with argon and palladium on charcoal (0.01869 g, cat.) was added. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 4 h. The reaction mixture was filtrated through celite and the filtrate was concentrated under vacuum. The solid was taken-up in water (20 mL) and acidified with HCl until reaching pH 1. The mixture was extracted with diethyl ether (10 mL) and the aqueous layer was basified with NaHCO.sub.3. The mixture was extracted with dichloromethane (310 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to afford N-ethyl-N-[5-methoxy-2-methyl-4-[2-(trifluoromethyl)tetrahydrofuran-2-yl]phenyl]-N-methyl-formamidine (Compound 1.22, 98 mg, 0.29 mmol).

(23) .sup.1H-NMR (400 MHz, DMSO): =7.72 (1H, s), 7.27 (1H, s), 6.48 (1H, s), 3.77 (4H, s), 3.33 (2H, m), 2.99 (3H, br s), 2.64 (1H, ddd), 2.38 (1H, dt), 2.10 (3H, s), 2.00 (2H, m), 1.14 (3H, m).

(24) Table E: Physical (LC/MS) Data of Certain Compounds of Formula (I)

(25) LC/MS (Liquid Chromatography Mass Spectrometry) Method Used:

(26) (ACQUITY UPLC from Waters, Phenomenex Gemini C18, 3 m particle size, 110 Angstrm, 303 mm column, 1.7 mL/min., 60 C., H.sub.2O+0.05% HCOOH (95%)/CH.sub.3CN/MeOH 4:1+0.04% HCOOH (5%)2 min.CH.sub.3CN/MeOH 4:1+0.04% HCOOH (5%)0.8 min., ACQUITY SQD Mass Spectrometer from Waters, ionization method: electrospray (ESI), Polarity: positive ions, Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature ( C.) 150, Desolvation Temperature ( C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700)).

(27) TABLE-US-00010 Compound No. Name Structure LC/MS 1.21 N-ethyl-N-[5-methoxy-2- methyl-4-[2- (trifluoromethyl)oxetan-2- yl]phenyl]-N-methyl- formamidine Rt = 0.64 min; MS: m/z = 331 (M + 1) 1.22 N-ethyl-N-[5-methoxy-2- methyl-4-[2- (trifluoromethyl)tetrahydro furan-2-yl]phenyl]-N- methyl-formamidine Rt = 0.65 min; MS: m/z = 345 (M + 1)

BIOLOGICAL EXAMPLES

(28) Blumeria graminis f. Sp. Tritici (Erysiphe graminis f. Sp. Tritici)/Wheat/Leaf Disc Preventative (Powdery Mildew on Wheat)

(29) Wheat leaf segments cv. Kanzler were placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks were inoculated by shaking powdery mildew infected plants above the test plates 1 day after application. The inoculated leaf disks were incubated at 20 C. and 60% rh under a light regime of 24 h darkness followed by 12 h light/12 h darkness in a climate chamber and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check leaf segments (6-8 days after application).

(30) The following compounds gave at least 80% disease control at 200 ppm in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development:

(31) 1.21 and 1.22

(32) Phakopsora pachyrhizi/Soybean/Leaf Disk Preventative (Soybean Rust)

(33) Four-week old soybean plants are sprayed in a spray chamber with the formulated test compound diluted in water. Leaf disks are cut from treated plants and placed on agar into 24-well plates one day after application. Leaf disks are inoculated by spraying them with a spore suspension on their lower leaf surface. After an incubation period in a climate cabinet of 24-36 hours in darkness at 20 C. and 75% rh, the leaf disks are then kept at 20 C. with 12 h light/day and 75% rh. The percentage leaf disk area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (12-14 days after application).

(34) The following compounds gave at least 80% disease control at 200 ppm in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development:

(35) 1.21 and 1.22

(36) Puccinia recondita f. Sp. Tritici/Wheat/Leaf Disc Preventative (Brown Rust)

(37) Wheat leaf segments cv. Kanzler were placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks were inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf segments were incubated at 19 C. and 75% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (7-9 days after application).

(38) The following compounds gave at least 80% disease control at 200 ppm in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development:

(39) 1.21 and 1.22

(40) Puccinia recondita f. Sp. Tritici/Wheat/Leaf Disc Curative (Brown Rust)

(41) Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format). The leaf segments are inoculated with a spore suspension of the fungus. Plates were stored in darkness at 19 C. and 75% rh. The formulated test compound diluted in water was applied 1 day after inoculation. The leaf segments were incubated at 19 C. and 75% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (6-8 days after application).

(42) The following compounds gave at least 80% disease control at 200 ppm in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development:

(43) 1.21 and 1.22